LU86345A1 - NOVEL BENZOFURAN DERIVATIVES, PROCESSES FOR THEIR PREPARATION AND DRUG AND COSMETIC COMPOSITIONS CONTAINING THEM - Google Patents

Description

s f *

NOVEL BENZOFURAN DERIVATIVES, THEIR PREPARATION METHODS AND DRUG AND COSMETIC COMPOSITIONS

r CONTAINER.

The invention relates to new chemical compounds composed of benzofuran derivatives, as well as preparation methods making it possible to obtain these new compounds. The invention also relates to the use of these new compounds, either in cosmetics or in medicine (human and veterinary) in pharmaceutical preparations intended for the treatment of skin conditions linked to a disorder of keratinization (differentiation-proliferation) , for the treatment of dermatological or other affections, with an inflammatory and / or immuno-allergic component, for the treatment of atopy, whether cutaneous or respiratory, for the treatment of degenerative diseases of connective tissue and tumors , in the treatment of rheumatoid psoriasis, as well as in pharmaceutical preparations for the ophthalmological field, in particular in the treatment of corneopathies.

The therapeutic action of vitamin A in its acid, aldehyde or alcohol form is well known in dermatology (see in this regard the publication "EXPERIENTIA”, volume 14, pages 1105-1119 (1978)); this action in the treatment of skin overgrowth, acne, psoriasis and the like, will be referred to hereinafter by the generic term "retinoid-like action." Products having a structure similar to vitamin A have been found to exhibit also a retinoid-like action, but that the side effect of toxic hypervitaminosis could, for certain compounds, be multiplied by a factor 30 more small than the multiplicative factor of the retinoid effect that sought (see in this regard "EUR J. MED CHEM.-CHIMICA THERAPEUTICA, January-February 1980, 15, number 1, * pages 9-15); P. L0ELIGER AND COLL, have described, in this ~ last publication, a derivative of formula (i_):

- X

--- (1) 2 5

The unsaturated side chain of this compound of formula (i) is identical to that of natural retinoic acid of formula (ii):; A family of compounds with retinoic action corresponding to general formula (iii) is also known from German patent application No. 2 437 607:

R

20 y ji (iii) R5 3 4 25 formula wherein the substituents R and R, among others, can together form a benzene nucleus joined to the first. The presence of a 3,7-tetraene dimethyl side chain is noted, which is the same as that of the compounds (i) and (ii) above.

3Q We also know, from German patent n ° 3 121 091, a compound with anti-seborrheic action, corresponding to the general formula (iv): 3 * r • U.

formula in which R ^ and R ^ can also together form a benzene ring joined to the first.

Also known from US Patent No. 3,755,604 is a process for reducing the production of sebum 10 using a 2-trans-4-trans-pentanedienoic acid of formula (v):

yv JL ^ C00H

(v).

It has been found, according to the invention, that the naphthalene nucleus of formulas (iii) 20 and (iv) can be replaced by a nucleus of formula: eca 25 which consists of a 2,3,4,4a-tetrahydro nucleus -4a, 10,10-trimethyl-1H-3,9b-methano dibenzofuran, which will be designated in the following by "TTMDBF", without losing the benefit of the retinoic action.

V

'<4? The subject of the invention is the triel-new industrial product which constitutes a new chemical compound * corresponding to the general formula (I): 5 "1" 3 1 * 5 d * 7 [[i ^ Vt-Rs a— (I >

Jj J ρβ J ^ Cr pd R2 R4 Rg Rg formula in which r - a, b, c, d and e are integers that can take, independently of one another, the values 0 or 1, .j with the condition that the sum a + b + c + d + e is greater than or equal to 2; - R, R2, R ^, R ^, R,., Rg, R ^ and Rg represent, independently, a hydrogen atom, a C ^ -Cg alkyl radical; 2q - Rg represents: - a radical -C == N; - an oxazolinyl radical; - a radical corresponding to formula (II): 25 "CH20R10 (II) 'formula in which R1Q represents a hydrogen atom, a C ^ -Cg alkyl radical, a mono- or polyhydroxyalkyl C ^ -C ^ radical , 2Q a cyclopentyl radical, a cyclohexyl radical, R10 possibly also representing a tetrahydropyranyl radical;

• V

5 - a radical corresponding to the formula (III) -CpR11 (III), 5 formula in which represents: - a hydrogen atom; 10 - a C 1 -C 4 alkyl radical; A. X ', - a radical -fT, where R' ^ R "and R", identical or different, represent a hydrogen atom, an alkyl radical Cj-Cg, an alkenyl radical C ^ -Cg, a cyclopentyl radical or cyclohexyl or alternatively an optionally substituted aralkyl or aryl radical, R ′ and R ″ being able to form a heterocy-key with the nitrogen atom to which they are attached, the radical ^ R ′ 35 -N being able to form , in addition, be \ R "the remainder of an amino acid or an amino sugar; - a radical -OR ^, where R ^ re_ 30 has a hydrogen atom, an alkyl radical in C ^ -C ^ q, a mono- or polyhydro-xyalkyl radical in C ^ -C ^, the group -OR ^ can also be derived from a sugar; as well as the salts and isomers of this chemical compound.

6 * - "·

Among the alkyl radicals in particular * which can be used in the meanings of the radicals with R ^ ^, R * and R ", mention may be made of the methyl, ethyl, isopropyl, butyl and tert-butyl radicals, and, preferably, for R ^ 5 at Rg, the methyl radical.

Among the C1-C20 alkyl radicals which can be particularly used in the meanings of the radical R.sup.1, mention may preferably be made of methyl, ethyl, propyl, 2-ethylhexyl, octyl, dodecyl, hexadecyl and octadecyl radicals. Among the substituted or unsubstituted aryl radicals which are particularly useful in the meanings of the radicals R ′ and R ′, the phenyl radical optionally substituted by a halogen atom, a hydroxyl or a C 1 -C 6 alkoxy radical is preferred.

Among the substituted or unsubstituted aralkyl radicals which are particularly useful in the meanings of the radicals R ′ and R ″, the benzyl or phenyl-radical are preferred, optionally substituted by a hydroxyl group or a C 1 -C 6 alkoxy group.

When the radicals R ′, R ″ and represent a mono- or polyhydroxyalkyl radical in C2-Cg, this is preferably a radical hydroxy-2 ethyl, dihydroxy-2,3 propyl or the residue of pentaerythritol.

Among the C 1 -C 6 alkenyl radicals which can be used in the meanings of the radicals R * and R ", there may be mentioned, in particular, the radicals propenyl, butenyl and isopen-tenyl.

When the radicals R 'and R "form a heterocy-key with the nitrogen atom to which they are attached, this is preferably a piperidino, morpholino, piperazino, pyrrolidino or (2-hydroxyethyl) radical. ) -4 pipéra-- zino.

When the group -OR ^ is derived from a sugar, the latter is, for example, glucose, mannitol or erythritol.

7

The compounds of formula (I) or their isomers can be in the form of their salts; they may be either zinc salts, an alkali or alkaline earth metal or an organic amine when they contain at least one free acid function, or salts of a mineral or organic acid , especially hydrochloride, hydrobromide or citrate, when they contain at least one amine function.

- Among the particularly preferred compounds 10 according to the invention, there may be mentioned those which correspond to the general formulas (la), (Ib), (le), (Id), (le), (If): CH3 0 ch3 ch3 o eçoAU ^ - '* (m 0

25 II

T3 fY0 '"* - ** ·

Jjs— <lc) 30 '<8 * CHj CHj j | . ....

o

II

15 ch3 ch3 or „20 in which R12 represents a hydrogen atom, an alkyl radical in C-pC ^ Q or a mono- or polyhydroxyalkyl radical in O ^ -C ^ and R 'and R", identical or different, represent a hydrogen atom or a C 1 -C 6 alkyl radical.

Among the preferred compounds of formula (la), mention may be made of the following two compounds: (Ethoxycarbonyl-4-methyl-3-butadiene-1E, 3Ë] -yl-2-TTMDBF,. (Îarboxy-4-methyl-3-butadiene-lE, 35J -yl-2-TTMDBF,

Among the preferred compounds of formula (Ib), mention may be made of the following two compounds: [lthoxycarbonyl-7-methyl-6-heptatriene-2E, 4E, 6Ë] -yl-2-TTMDBF,. {Arboxy-7-methyl-6-heptatriene-2E, 4E, 6 |] -yl-2-TTMDBF.

Among the preferred compounds of formula (Ie), there may be mentioned the following two compounds:

35. [t-Methoxycarbonyl-4 '-phenyl) -2-methyl-1 -ethene- 1 | Q-yl-2-TTMDBF

j (Carboxy-4 '-phenyl) -2-methyl-1-ethene- 1ETJ-yl-2-TTMDBF.

9

Among the preferred compounds of formula (Id), mention may be made of the following two compounds:. Qsthoxycarbonyl-8-dimethyl-3,7-octatetraene-1E, 3E, 5E, 7E] -yl-2- TTMDBF. (Carboxy-8-dimethyl-3,7-octatetraene “1E, 3E, 5E, 7Ë] -yl-2-TlM) BF.

Among the preferred compounds of formula (Ie), the following two compounds may be mentioned: [(Methoxycarbonyl-4'-phenyl) -A-methyl-3-butadiene-1E, 3ïï] -yl-2-TTMDBF,. [ÏCarboxy-A'-phenyl) -4-methyl-3 butadiene-1E, 3E] -yl-2-TTMDBF.

Among the preferred compounds of formula (If), mention may be made of the following compound: | Ethylaminocarbonyl-7-methyl-6 heptatriene-2E, 4E, 6Ê] -yl-2-TTMDBF.

A subject of the invention is also the processes for preparing the new compounds of formula (I).

According to the invention, the synthesis of the compounds of formula (I) consists: - or else of reacting a compound of formula (IV): 25 on a compound of formula (V): ^ 5 H7 r2 r4 r6 r8 10 - or else react a compound of formula (VI):: *

Ri R3 5 f (| (VI) r2 on a compound of formula (VII): R5 R7 10 [1 1 JL JL ΊΓ (seen) r4 r6 r8 15 - or else to react a compound of formula (VIII): gçoVf · - 25 - on a compound of formula (IX): r7 b. JL (IX) 30 J · r6 r8 formulas in which a, b, c, d, e, R ^, R2, R ^, R ^, R ^, 35 Rg, R ^, R0 and Rg have the meanings indicated above, with the conditions, on the one hand, that the sums 11 b + c + d + e; c + d + e; and d + e, in the formulas respectively (V), (VII) and (IX) are each greater than or equal to 1, and, on the other hand, that Rg cannot represent the group of formula (III): ~ P1 o 10 when is a hydrogen atom or a CpCg alkyl radical, groups A and B in formulas (IV) and (V); (VI) and (VII); (VIII) and (IX) above representing one a oxo group, while the other is: a) or a triarylphosphonium group of formula (X): -p [x] 3 ï® (X), formula in which X is an aryl group and Y is 2 ° an anion monovalent of an organic acid or in organic ; b) or else a dialkoxyphosphinyl group of formula (XI): “--fl 0 formula in which Z represents a C1-Q- alkoxy residue.

I Ö

When A and B represent, one an oxo group, and the other a triarylphosphonium group, the reaction of the compounds (IV) and (V) or of the compounds (VI) and (VII) or of the compounds (VIII) is carried out ) and (IX), in the presence of an alkali metal alcoholate, such as sodium methylate, in the presence of an al-cud metal hydride, such as sodium hydride, in the presence of 12-butyl lithium in a solvent such as tetrahydrofuran or »dimethylformamide, or else in the presence of an alkalin carbonate such as potassium carbonate in an alcohol such as isopropanol, or alternatively in the presence of an aluminum oxide 5 kylene, optionally substituted by an alkyl group, in particular in a solvent such as dichloromethane, the reaction temperature being between -80 ° C. and the boiling temperature of the reaction mixture.

When A and B represent, one, an oxo group and the other, a dialkoxyphosphinyl group, the reaction of the compounds (IV) and (V) or of the compounds v (VI) and (VII) is carried out or compounds (VIII) and (IX) in the presence of a base and, preferably, in the presence of an inert organic solvent; the reaction can be carried out, for example, using sodium hydride in benzene, toluene, dimethylformamide, tetrahydrofuran, dioxane or 1,2-dimethoxyethane, or also using an alcoholate, for example by means of sodium methylate in methanol; the condensation can also be carried out using a mineral base, such as potassium hydroxide or sodium hydroxide, in an organic solvent such as tetrahydrofuran, or also by means of an alkali carbonate, for example by means of potassium carbonate in water, or by means of butyllithium in tetrahydrofuran. A crown ether capable of complexing the metal cation contained in the base can be added to the reaction mixture, which makes it possible to increase the strength of the latter. The reaction is preferably carried out in a temperature range between 30 -80 ° C and the boiling point of the reaction mixture.

The condensation of the compound of formula (IV) with the compound of formula (V) is particularly suitable for the synthesis of the compounds of formula (la), (le) and (le).

The condensation of the compound of formula (VI) with the compound of formula (VII) is particularly suitable for the synthesis of the compounds of formula (Ib).

The condensation of the compound of formula (VIII) on the compound of formula (IX) and very particularly suitable for the synthesis of the compounds of formula (Id).

The compounds of formula (IV) to (IX) are known compounds or can be prepared by known methods.

The compound of formula (I) obtained by the preparation methods according to the invention can undergo functional modifications of the substituent Rg. Among the functional modifications of this substituent Rg, mention may be made, for example, of the preparation of alcohols, acids and their salts, and amides from the corresponding esters. All these functional modifications can be carried out by procedures known per se.

The compounds of formula (I) are obtained in the cis / trans mixture which can be separated, if desired, in a manner known per se, into the cis compounds and trans or isomerized into fully compounds trans.

The compounds of formula (I) have been found to exhibit good to excellent activity in the test for inhibition of ornithine decarboxylase after induction, by "tape stripping", in the naked rat. (Martine BOUCLIER et al. - Dermatologica 169, n ° 4 (1984)). This test is accepted as a measure of the action of retinoids on the phenomena of cell proliferation.

The compounds of formula (I) also exhibit = enhanced activity in the differentiation test of mouse embryonic teratocarcinoma cells (cellu-i F9: "Cancer Research" 43, page 5268, 1983 ·).

35 i

U

Finally, the compounds according to the invention exhibit - an excellent comedolytic activity in the rhino mouse test described by BUNNE and al. in International Journal of Cosmetic Science ^ 3, 23-28 (1981).

5 The compounds of formula (I) are therefore particularly suitable for treating ---------------------- ter dermatological conditions linked to a disorder of keratinization (differentiation -proliferation) as well as dermatological or other affections with an inflammatory and / or immuno-allergic component, and in particular for treating acne vulgaris, comedonian or polymorphic, senile acne, solar acne and medicinal or professional acne, extended forms and / or severe psoriasis and other keratinization disorders, 15 and, in particular ichthyosis and ichthyosiform states, Darier's disease, palmoplantar keratoderma, leukoplakia and leukoplasiform states, lichen planus, all benign dermatological proliferations or malignant, severe or extensive; they are also active against rheumatoid psoriasis; - ----------------------- ------------- they can be used in the treatment of cutaneous atopy as eczema or respiratory atopy; they can be recommended in dystrophic epidermolysis bullosa and in the molecular pathology of collagen; they also find an indication in carcinomas induced by ultraviolet rays (solar carcinogenesis), in epidermodysplasia verruciformis and related forms; finally, they find an application in the ophthalmological field, in particular for the treatment of corneopathies.

The subject of the present invention is therefore also! 15 a new medicinal composition, intended in particular for the treatment of the abovementioned conditions, characterized in that it comprises, in a pharmaceutically acceptable carrier, as active substance (s), at least 5 a compound of formula (I) and / or at least one of its isomers and / or at least one of its salts.

When the compounds of formula (I) are used topically, a good activity of these is observed over a very wide range of dilution; it is possible to use, in particular, concentrations of active substance (s) ranging from 0.0005% to 2% by weight. It is of course possible to use higher concentrations, when this is necessary for a particular therapeutic application; however, the preferred concentrations of active ingredient are between 0.002 and 1% by weight.

The topical compositions are advantageously in the form of ointments, gels, creams, ointments, powders, tinctures, solutions, sus-20 pensions, emulsions, lotions, sprays, patches or soaked pads. The compounds in question are mixed with inert non-toxic supports, generally liquid or pasty, suitable for topical treatment.

The abovementioned pharmaceutically active substances can be used enterally. By oral route, said active substances are administered at a rate of approximately 2 dH g up to 2 mg per day per kg of body weight; an excessive dosage may manifest itself in the form of a hypervitaminosis A recognizable by its symptoms and which can give rise to fear of hepatic toxicity necessitating biological control of the hepatic function. The required dose can be administered in one or more doses. For oral administration, the 35 * 16 suitable forms are, for example, tablets, capsules, dragees, syrups, suspensions, emulsions, solutions, powders, granules; a preferred mode of administration is the use of capsules containing from 0.1 mg to about 1 mg of active substance (s).

The pharmaceutically active substances can be administered parenterally, in the form of solutions or suspensions for intravenous or intramuscular infusions or injections. In this case, said active substances are administered at a rate of approximately 2 μg up to 2 mg per day per kg of body weight; a preferred mode of administration consists in using solutions or suspensions containing from 0.01 mg to 1 mg approximately of active substance (s) per ml.

When the pharmaceutically active substances are used by the ocular route, they are advantageously in the form of solutions or powders to be diluted for eye drops.

The pharmaceutically acceptable carrier can comprise water, gelatin, lactose, starch, talc, petroleum jelly, gum arabic, polyalkylene glycols, magnesium stearate. Tablets, powders, dragees, granules or capsules can contain binders, fillers, powdery supports. Solutions, creams, suspensions, emulsions or syrups may contain thinners, solvents, thickeners.

The compounds of formula (I), as well as the salts and the isomers of these compounds, also find an application in the cosmetic field, in particular, in personal and hair hygiene and, in particular, in treatment. acne-prone skin, physiologically dry skin, seborrhea, hair loss, for hair regrowth, to combat the oily appearance of the skin or hair. They also have a preventive and curative power against the harmful effects of the sun.

* The present invention therefore also relates to a new cosmetic composition, characterized in that it comprises, in a cosmetically acceptable ac-5 support, as active substance (s), at least one compound of formula (I ) and / or at least one of its isomers and / or at least one of its salts; this composition can be in the form of a lotion, gel, cream, soap, shampoo or the like.

The concentration of cosmetically active substance (s) is between 0.0005 and 2% by weight and preferably between 0.01 and 1% by weight relative to the total weight of the composition.

In the treatment of the abovementioned disorders, the compounds according to the invention, used in the compositions defined above, act ----------- by increasing the follicular epithelial production of non-adherent cells, dislodging thus and removing the contents of the acne comedone. These compounds reduce the size of the sebaceous glands and partially inhibit the secretion of sebum.

The compositions according to the invention can contain inert additives, or pharmacodynamically or cosmetically active additives and, in particular, hydra-

pC

3 aunts, such as thiamorpholinone and its derivatives or urea; anti-seborrhérique agents, such as S-carboxylmé-thyicvstéine, S-benzyl-cystéamine, their salts and their derivatives, tloxolone; anti-acne agents such as benzoyl peroxide; antibiotics, such as erythromycin and its esters, neomycin, tetracyclines ^ or polymethylene -4,5 isothiazolones-3; agents promoting hair regrowth such as "Minoxidil" (2,4-diamino-6 piperidino-6 pyrimidine oxide-3) and its derivatives, anthralin and its derivatives, "Diazoxide" (chloro-7-me-35 18 : . he

J

3-thyl-benzothiadiazine-1,2, A dioxide-1,1), "Phenytoin T '(diphenyl-5,5 iraidazolidinedione-2, A) or oxa-propanium iodide; steroidal anti-inflammatory agents and non-steroidal; carotenoids and, in particular, 5 ^ -carotene; anti-psoriatic agents such as anthralin and its derivatives, eicosatetraynoic-5,8,11,14 and -triynoic-5,8 acids, 11, their esters and their amides.

The compositions according to the invention may also contain flavor enhancers, preservatives, stabilizers, moisture regulators, pH regulators, osmotic pressure modifiers, agents emulsifiers, UV-B and UV-A filters, antioxidants such as c-tocopherol, butylhydroxy-anisole or butylhydroxy-toluene.

To better understand the object of the invention, we will now describe several embodiments.

20 EXAMPLE 1

Preparation of a compound of formula: CHj CH3 25 a) preparation_of_compound de_formule_: 30 35 This product is obtained according to procedure 19! described by J.L. FRY and W.J. WEST, J. Org. Chem. 1981, c. 46 (10) 2177-2179- * Λ 20 b) B! - !! PË £ Ëbi0! 2_dl; 1 compound of formula:

A solution of 9> 2 g of composition obtained in a) and 3.2 cm of acetyl chloride in 3 are slowly added.

60 cm of dichloromethane to a solution * 10 cooled to -10 ° C of 6g of aluminum chloride in 60cmJ

dichloromethane. The mixture is stirred for two hours while allowing the reaction mixture to return to ambient temperature. Poured onto a saturated ammonium chloride solution and the organic phase is extracted with ether. The organic phases are combined, dried over sodium sulfate and the solvent is distilled under reduced pressure. The residue obtained is recrystallized from ethanol.

A compound is obtained having the following characteristics:

20 - Melting point: 139 ° C

{) vnax = 291 nm £ - 14230

Elementary analysis: 25 ELEMENTARY ANALYSIS__C__H__0

Calculated .............. 79.96 8.20 1 1.84

Found ............... 80.01 8.20 1 1.68 30 c) preparation of the compound of f2 ^ mule: CH3 „ecch" * 21 10g of the compound obtained in b) and 7 , 2 g of diethyl cyanomethylphosphonate are dissolved in 40 cm of tetrahydrofuran. This solution is added to a suspension.

O

board of 4 g of potash crushed in 60 cm of tetrahydrofuran. Stirred for 2 hours at room temperature, then diluted with 500 cm of toluene. We filter on celite. After evaporation of the solvent, and recrystallization from ethanol, 8 g of expected product are obtained having the following characteristics: 10 - UV spectrum (chloroform): Xmax = 313 nm

ELEMENTARY ANALYSIS C j H 0 d N

Calculated .............. 81.87 7.90 5.45 4.77 15 Found ............... 81.89 8.00 5.60 4.85 d) pr] spacing of the compound of formula: ch3 'act · "' 2 ^ A solution of 2.93 g of compound obtained in c) is cooled to -78 ° C in 50 cm3 of a mixture 50 : 50

O

toluene-hexane. 12 cm of 1M solution of diisobutyl aluminum hydride in toluene are added. The mixture is stirred for 3 hours, allowing the temperature to rise to 0 ° C. The mixture is cooled to -78 ° C. and 30 g of deactivated silica gel are added with 6 cm 3 of water suspended in a 50:50 ether-hexane mixture. It is allowed to return to room temperature in one hour, then filtered. The silica gel is washed with ether.

After evaporation of the solvent and recrystallization from isopropyl ether, the expected product 22 is obtained in the form of white crystals having the following characteristics:

- Melting point: 102 ° C

^ - UV spectrum (chloroform): ~ 206l () m ELEMENTARY ANALYSIS C H 0

Calculated .............. 81, OA 8.16 10.80 10 Found ............... 81.08 8.21 10.76 e) preparation of the compound of formula: ch3 ch3 C02C2H5 20 A solution of 1.5 g of 3 3 ciisopropylamine and 6 cm of 2.5M butyllithium in 25 cm of tetrahydrofuran is cooled to -50 ° C. 25 cm of hexamethylphosphoramide is added, followed by 3 μg of diethyl ethoxycarbonyl-3-methyl-2-propen-2-ylphosphonate in 5 cm of tetrahydrofuran. The mixture is stirred for one hour at -50 ° C, then cooled to -78 ° C.

Cn is added 3 g of compound obtained in d). After one hour at -78 ° C, it is allowed to return to room temperature. The reaction mixture is diluted with a saturated solution of ammonium chloride. The aqueous phase is extracted with ether. The 30 organic phases are combined, washed with water and dried over sodium sulfate. The solvent is distilled under reduced pressure and the residue is chromatographed on silica gel (solvent: hexane + 1 to 3% ethyl acetate). After recrystallization from hexane, 1.6 g of expected product 35 is obtained having the following characteristics: 23

- Melting point: 92 ° C

o +. nu / ui \ C Amax = 367 nm - UV spectrum (chloroform) :) L £. = 39390 * '5 --- r--

I 1 I

BASIC ANALYSIS * C H 0!

Calculated ............. 79.76 8, A3 11.81

Found .............. 79.78 8.45 1 1.65 10 ---- f) preparation of the compound of formula: ch3 ch3

A solution is heated for 1 hour at 60 ° C.

O

1.4 g of compound obtained in e), 1 g of potassium hydroxide in 20 cm 20 3 of water and 20 cm of ethanol. The ethanol is distilled and then acidified with 2N hydrochloric acid. It is filtered, washed with water and recrystallized from acetone. 1 g of expected product is obtained having the following characteristics:

- Melting point: 240 ° C

^ /) \ max = 352 nm

- UV spectrum (methanol): J

= 3700C

ELEMENTARY ANALYSIS C H ’0 30 i

Calculated ................ 79.33 8.06 12.68

Found ................. 79.36 8.08 12.58 35 i! *

2A

EXAMPLE 2

Preparation of a compound of formula: ch3 5 a) preparation of the compound of formula: 10 ------------------------------- - 0 15. 3

An 11 cm solution of

O

titanium tetrachloride in 100 cm of dichloromethane. Is introduced in AO minutes, maintaining the temperature at -30 ° C, a mixture of 11, A g of compound obtained in Example 20 1a) and A, A cm '"of dichloromethyl methyl ether. Stirred for one hour at -20 ° C., then for two hours at room temperature The reaction mixture is poured onto ice water and the organic phase is washed with water After evaporation of the solvent and recrystallization from hexane, 6 are obtained. , 7 g of expected product having the following characteristics:

- Melting point: 1A0 ° C

- UV spectrum (chloroform): i "^ max" nm L £ = 16 190 30 ELEMENTARY ANALYSIS CH 0

Calculated .............. 79.65 7.56 12, A8

Found ............... 79.53 7.90 12.33 “35 _1 __ 25 b) P £ §paration_of the compound of_formula: ch3

$ pO ^ “! CA

This compound is obtained according to the procedure described in Example 1e) in which the compound of Example '' d) is replaced by the compound of Example 2a). The expected product is purified by chromatography on solvent silica gel: hexane with 2% ethyl acetate). It has the following characteristics:

- Melting point: 73 ° C

15 rv „„ „,,,„, \ Xrnax = 347 nm

- UV spectrum (chloroform): J

L £ = 31400 ELEMENTARY ANALYSIS C, H 0 20 Calculated ........... 78.69 8.20 13.1 1

Found ............ 78.53 8.23 13.24 c) preparation_of_the_compound_formule:

This compound is obtained according to the procedure described in example If *), in which the compound of example 1e) is replaced by the compound of example 2b). It has the following characteristics: 35 26

- Melting point: 160 ° C

max = 347 nm £. = 22500 5 ELEMENTARY ANALYSIS C H 0

Calculated ................. 78.1 1 7.69 14.20

Found .................. 78.46 7.79 14.43 I________ 10 s EXAMPLE 3

Preparation of a compound of formula: a) preparation of the compound of formula: 2 ° pc 5.4 g of product obtained in Example 1b) are suspended in 30 cm of methanol and 2 cm of water. 0.6 g of sodium borohydride is added and the mixture is stirred at temperature for 16 hours. The reaction mixture is poured onto ice. The precipitate and the aqueous phase are extracted with 3 times 60 cm of ether. The organic phase is dried over sodium sulfate and the solvent is distilled under reduced pressure. 5.7 g of product are obtained which is redissolved in 50 cm of petroleum ether. The solution is cooled to -10 ° C and 35 ', 83 g of phosphorus tribromide are added over approximately 30 minutes, keeping the temperature below -10 ° C. After the addition of phosphorus tribromide 27, the mixture is stirred for 12 hours at room temperature. The reaction mixture is poured onto ice. Extraction is carried out with 3 times 60 cm of ether. The organic phase is washed with an aqueous solution of sodium bicarbonate, then with a saturated solution of sodium chloride.

After drying over sodium sulfate, then evaporation of the solvent, 5.5 g of yellow crystals are recovered which are

O

dissolved in 50 cm of toluene. 4.1 g of triphé-nylphosphine are added, the mixture is stirred for 12 hours at ambient temperature, then for 6 hours at 55 ° C. The mixture is allowed to cool, then the precipitate is filtered, washed with hexane and dried. 6.5 g of a pale yellow product are obtained which is redissolved 3 in 100 cm of isopropanol. 1.7 g of methyl paraformyl benzoate and 2 g of potassium carbonate are added. The mixture is heated for 4 hours at reflux. It is cooled, then filtered and the solvent is concentrated under reduced pressure. The residue is purified by chromatography on silica gel (solvent: hexane-ethyl acetate: 98-2).

The product obtained has the following characteristics:

- Melting point: 130 ° C

ÎÀmax = 325 nm - t = 22000 y- (25 ELEMENTARY ANALYSIS C H! 0 | j-

Calculated ............. 80.56 7.51 1 1.92

Found .............. 80.61 7.49 1 1.97 2Q b) preparation of the compound_of formula:

^ —MgH

28

This compound is obtained according to the procedure * described in Example 1f) in which the compound of Example 1e) is replaced by the compound of Example 3a). r The product obtained has the following characteristics:

- Melting point: 240 ° C

ΓXmax = 312 nm - UV spectrum (acetic acid) ^ L = 22900 10 ELEMENTARY ANALYSIS C H; 0 7. __I___j_

Calculated ............... 80.38 7.26 12.35

Found ................ 80.19 7.30 12.65 15 EXAMPLE 4

Preparation of a compound of formula: CH 3 CH 3 0 2 0n is stirred for 15 minutes a mixture of 0.6 cm ^ of thionyl chloride and 2.2 g of imidazole in 20 cm ^ of tetrahydrofuran. It is filtered, then the precipitate is washed with 10 cm of tetrahydrofuran. The filtrate and the washing solvent are combined. 2 g of compound obtained in example (if) are added and the mixture is stirred at ambient temperature for 2 hours. 1 cm of ethylamine is added and the mixture is stirred for 15 minutes. The reaction mixture is poured into water. After extraction with ether, distillation of the solvent under reduced pressure and recrystallization from ethanol, 1.87 g of the expected product is obtained having the following characteristics:

- Melting point: 141 ° C

fXrnax: 353 nm - UV spectrum (methanol): /: 43800 5 ^ ELEMENTARY ANALYSIS ö ü ü ö c27H35N ° 2, 0.25 H20 _

Calculated ............ 79.08 8.73 3.42 8.78

Found ............. 78.91 8.61 3.39 8.56 10 EXAMPLE 5

Insoluble tablets of 0.5 g each are prepared, having the following formulation: - Compound of Example 3b) .................. 0.050 g - Lactose. .................................. 0.082 g - Stearic acid ........... ................ 0.003 g - Purified talc ............................. 0.015 g 2Q - Sweetener.qs

- Dye ... q.s.

- Rice starch. .q.s ....................... 0.500 g

These tablets are obtained, each containing 0.05 g of active principle by direct dry compression of the mixture of the various constituents. These tablets are administered at a rate of 2 to 4 tablets per day in the treatment of psoriasis. The improvement is visible between the 30th and 60th day of treatment, depending on the severity of the cases treated.

30 EXAMPLE 6

A gel is prepared for a topical application by carrying out the following formulation: * “30 - Compound of Example 1fi ............. 0.05 g - Ethanol ....... ....................... 43.00 g - tfC-tocopherol ............. 0.05 g - Polymer high molecular weight acrylic acid, sold under the name

"CARB0P0L 941" by the company "GOODRICH

CHEMICAL Co "................................... 0.50 g - Triethanolamine in 20% aqueous solution ................................ 3.80 g 10 - Water ........... ....................... 9.30 g ~ - Propylene glycol ... qs .............. 100, 00 g

This gel is applied to dermatosis skin or to acne skin at the rate of 1 to 3 times a day and there is a significant improvement within a period of between 4 and 12 weeks depending on the severity of the case treated.

EXAMPLE 7

A sunscreen cosmetic composition is prepared by carrying out the following formulation: 20 - Compound of Example 2b) ............. 1.00 g - Benzylidene camphor ....... ........... 4.00 g - Triglycerides of fatty acids (Cg to C ^) .. 31.00 g - Glycerol monostearate ............. 6.00 g - Stearic acid ....................... 2.00 g 25 - Cetyl alcohol ........... ........... 1.20 g - Lanolin .............................. 4.00 g - Preservatives ......................... 0.30 g - Propanediol ................ ........... 2.00 g - Triethanolamine ....................... 0.50 g 30 - Perfume ... ............................. 0.40 g - Demineralized water ... q. s ............... 100.00 g

This composition is applied to the T face and body of a subject with sensitive skin before exposure to the sun. The application is repeated several times 35 times during exposure to the sun. It is found that this composition gives excellent protection to the treated skin.

_L

* \ 32 EXAMPLE 8

An anti-seborrheic cream is prepared by carrying out the following formulation: - Polyoxyethylene 5 stearate (40 moles of EO) sold under the name of "MYRJ 52" by the company "ATLAS" .......... ........... 4 g - Mixture of lauric esters of sor-bitol and sorbitan, polyoxyethylenated *. · 10 to 20 moles of EO sold under the name "TWEEN 20" by the company "ATLAS" ... 1.8 g - Mixture of glycerol mono and distearate sold under the name "GELEOL" by the company 15 "GATTEFOSSE" ................. .......... 4.2 g - Propylene glycol ........................ 10 g - Butylhydroxyanisole ...... .............. 0.01 g - Butylhydroxytoluene .................... 0.02 g - Keto-stearyl alcohol. ............... 6.2 g 20 - Preservatives .......................... qs - Perhydrosqualene ....................... 18 g - Mixture of capry-lique-capric triglycerides sold under the name "MIGLY0L 812" by the company "DYNAMIT NOBEL "................ 4 g - S-carboxymethylcysteine ................ 3 g - Trieth anolamine 99% .................... 2.5 g - Compound of Example 4 0.02 g - Water .......... ....................... qs 100 g 33 EXAMPLE 9

An anti-acne cream is prepared by mixing the following ingredients: - Mixture of glycerol stearates and 5 polyethylene glycol (75 moles) sold under the name "GELOT 64" by the company "GATTEFOSSE" ...... ....... 15 g - Polyoxyethylenated core oil with 6 moles of EO sold under the name of "LABRAFIL M 2130 CS"; by the company "GATTEFOSSE" ............. 8 g - Perhydrosqualene ........................ 10 g - Colorant ................................ qs - Preservatives .............. ............. qs _ Perfumes ................................. qs - Tioxolone ............................... 0.4 g - Polyethylene glycol 400 .......... ........ 8 g - Purified water ............................ 58.5 g - Disodium salt of l ethylenededia- tetracetic acid ....................... 0.05 g - Compound of Example 1f ......... ........ 0.02 g EXAMPLE 10

Preparing a hair lotion against hair loss and promoting hair regrowth by mixing the following ingredients: - Propylene glycol ....................... .. 20 g - Ethanol ................................. 34.92 g - Polyethylene glycol 400 .... .............. 40 g 30 - Water ............................... ...... 4 g - Butylhydroxyanisole ..................... 0.01 g - Butylhydroxytoluene ............. ........ 0.02 g - Compound of Example 1f ................. 0.02 g - Minoxidil ........ ....................... 1 g * 34 EXAMPLE 11

It is an anti-acne kit comprising two parts: a) a gel is prepared by carrying out the following formulation: - Ethyl alcohol ................. ...... 48.4 g - Propylene glycol ....................... 50 g - CARB0P0L 940 .......... ................ 1 g - Diisopropanolamine 99% ................ 0.3 gu 10 - Butylhydroxyanisole ..... .............. 0.05 g ^ - Butylhydroxytoluene ................... 0.05 g -oC-Tocopherol .. ........................ 0.1 g - Compound of Example 3 ............... 0.02 gb) a gel is prepared by carrying out the following formulation: - Ethyl alcohol ...................... 5 g - Propylene glycol. ..................... 5 g - Disodium salt of ethylenededia mine tetracetic acid ................ ..... 0.05 g 20 - CARB0P0L 940 .......................... 1 g - Triethanolamine 99% ..... .............. 1 g - Sodium lauryl sulfate ............... 0.1 g - Purified water ........ .................. 75.05 g - Benzoyl peroxide hydrated at 25% .... 12.8 g 25 The mixture of two gels will be done externally, weight for weight.

Claims (30)

35 1. Chemical compound corresponding to the general formula * (I): * R, R3 R5 R7 'i ^ SC ^ Re JJ J | Jal J ** cr pd 0 / Vi ^ & 2 r4 r6 r8 10 formula in which: - a , b, c, d and e are integers which can independently take the values 0 or 1, with the condition that the sum a + b + c + d + e is greater than or equal to 2 ; 15. R ^, R2> Rg, R ^, Rg, Rg> Ry and Rg represent, independently, a hydrogen atom, an alkyl radical in C - Cc I o J - Rg represents: - a radical -C -NOT ; 20. an oxazolinyl radical; - a radical corresponding to formula (II): -ch2or10 (II), formula in which R ^ g represents a hydrogen atom, a C ^ -Cg alkyl radical, a mono - or polyhydroxyalkyl C ^ - radical Cg, a cyclopentyl radical, a cyclohexyl radical, r 'R ^ g can also represent a tetrahydropyranyl radical; [36 - a radical corresponding to the formula (III)% · - C— Rin (III), »1 5 formula in which represents: - a hydrogen atom; - a C 1 -C 4 alkyl radical; - R '1 ° ^ - a radical -N, where \ r "R' and R", identical or different, represent a hydrogen atom, an alkyl radical in C ^ -Cg, an alkenyl radical in Cg-Cg, a cyclo-pentyl or cyclohexyl radical, or also an aralkyl or aryl radical, optionally subs-20 J / substituted (s), R ′ and R ″ which can form a heterocycle with the nitrogen atom to which they are attached, the radical 25 ^ R '—N can also be \ R »the remainder of an amino acid or an amino sugar; - a radical -OR ° where R ^ represents a hydrogen atom, a radical alkyl in r- a mono- or polyhydro- xyalkyl radical in C2 ~ Cg, the group- __ -0R1o can also 35 ^ be derived from a sugar; 37 * “as well as the salts and Isomers of this chemical compound. 2. Compound according to Claim 1, characterized in that: - the C 1 -C 4 alkyl radicals which are involved therein for the meanings of the radicals R 4 to R 4, R 'and RM, are chosen from the group formed by methyl, ethyl, isopropyl, butyl and tert-butyl radicals; - the alkyl radicals in there intervene for the meanings of the radical R12, ------------- „10 are chosen from the group formed by the radicals methyl, ethyl, propyl, 2-ethylhexyl, octyl , docecyle, hexadécy-le and octadécyle; - the mono- or polyhydroxyalkyl radicals C2 ~ Cg, which intervene there for the definition of R ', R "and R ^, are chosen from the group formed by the radicals hydroxy-2 ethyl, dihydroxy-2,3 propyl and rest of pentaerythritol; - the aryl or substituted aryl radicals which are involved in the definition of the radicals R * and R "are respectively phenyl or phenyl radicals substituted by a halogen atom, a hydroxyl or a Cj-Cg alkoxy radical ; - the aralkyl or substituted aralkyl radicals which are involved in the definitions of the radicals R 'and R ", are chosen respectively from the benzyl groups p ς Ό and phenethyl or from the benzyl and phenethyl groups substituted by a hydroxyl or an alkoxy radical in CrC6 '- C 1 -C 6 alkenyl radicals which are involved in the definitions of R' and R "are chosen from propenyl, butenyl and isopentenyl radicals; 38 η - the heterocycles, which are involved therein for the definition of -N, are chosen from piperidine, piperazine, morpholinic, pyrrolidine, and (2-ethyl 2-hydroxy) -4 piperazine rings ; - the group OR ^ "when it is derived from a sugar, is a residue of glucose, mannitol or erythri-tol. »10 3 - Compound according to one of claims 1 and 2,. * * In which at least one of the radicals' R ^ to Rg is an alkyl radical, characterized in that the said alkyl radical is a methyl radical . 4. Compound according to one of claims 1 to 3, said compound being a salt of a compound corresponding to formula (I) or of one of its isomers, characterized in that, if the compound of formula ( I) comprises at least one free acid function, said salt is chosen from the group formed by zinc, alkali or alkaline-earth metal or organic amine salts; and that, if the compound of 25 \ 30 \ 35 ^ - 39 formula (I) contains at least one amine function, said salt is chosen from the group formed by the salts of a mineral or organic acid and, in particular, the hydrochloride , bromhy-drate or citrate. 5. Compound according to claim 1, characterized in that it corresponds to the formula: ch3 0 "> formula in which R represents a hydrogen atom, an alkyl radical in CJ-C2Q or a mono- or polyhydro- radical C 1 -C 4 xyalkyl. 6. Compound according to claim 1, characterized in that it corresponds to the formula: ch3 ch3 0 formula in which R represents a hydrogen atom, a C 1 -C 4 alkyl radical or a mono- radical or C2 ~ C6 'poly-hydroxyalkyl 7. Compound according to claim 1, characterized in that it corresponds to the formula: 0 30 II 0-0 ^ lXTc "o'R, z IICl 35 formula in which represents a hydrogen atom, 4 ° ί" an alkyl radical in C ^ -C20 or a radlcal mono- or poly-hydroxyalkyl C ^ - C ^. 8. Compound according to claim 1, characterized in that it corresponds to the formula: 5 CH3 CH3 J 10 r formula in which represents a hydrogen atom, * an alkyl radical in C-j-C ^ q or a mono- or polyhyroxyalkyl radical in C ^ -Cg. 9. Compound according to claim 1, characterized in that it corresponds to the formula: formula in which represents a hydrogen atom, a C 1 -C 20 alkyl radical or a mono- or polyhy-droxyalkyl radical in C2 ~ Cg. 10 - Compound according to Claim 1, characterized in that it corresponds to the formula: CHj CH3 0 formula in which R 'and R ", identical or different, represent a hydrogen atom, or an alkyl radical in C1-C6 ·! 41 11. Process for the preparation of a compound of formula (I), characterized in that: - or else a compound of formula UV is reacted: on a compound of formula (V) 10 V a \ 5 42 r3 R5 j? 7 BVY I 6 (V) 5 & 2 r4 r6 r8 - or else a compound of formula (VI) is reacted: * 1 * 3 rOi [fx; i ^ i! Ï ^ T ^ SXA (vi) i * on a compound of formula (VII): 5 R5 ^ 7 (VII> r4 R6 r8 ^ - or else a compound of formula (VIII) is reacted: Ri R3 R5 25 '1 on a compound of formula (IX): 30 * 7 b. Il uL JÎ (IX ) ^ ΤΓμί ^ 5 r6 Re 35 4 43 {ί S v. Formulas in which a, b, c, d, e, R ^, R ^, Rg, R ^, Rg, Rg, R ^, Rg and Rg have the meanings indicated in claim 1, with the conditions, on the one hand, that the „sums b + c + d + e; c + d + e; etd + e, in the formulas respectively (V), (VII) and (IX) are each greater than or equal to 1, and, on the other hand, that Rg cannot represent the group of formula (III): —fj — Rn (III) „10 II 0 when R ^ is a hydrogen atom or a C 1 -C 6 alkyl radical, the groups A and B in formulas (IV) and (V); (VI) and (VII); (VIII) and (IX) above representing one an oxo group, while the other is: a) or a triarylphosphonium group of formula (X): -p [xJ3 @ Xe (X), formula in which X is an aryl group and Y is a monovalent anion of an acid o organic or inorganic; b) or else a dialkoxyphosphinyl group of formula (XI): 25. pf zj (XI), | L J2 0 formula in which Z represents an alkoxy residue in CL-Ch. io 3Q 12 - Process according to claim 11, wherein A and B represent, one, an oxo group, and the other, a triarylphosphonium group, characterized in that the reaction of the compounds (IV) is carried out and (V) or w of compounds (VI) and (VII) or of compounds (VIII) and (IX), 35 I - "fl *" · I 44 in the presence of an alkali metal alcoholate, such as methylate sodium, in the presence of an alkali metal hydride, such as sodium hydride, in the presence of butyl lithium in a solvent such as tetrahydrofuran or v 5 dimethylformamide, or else in the presence of an alkali carbonate such as potassium carbonate in an alcohol such as isopropanol, or alternatively in the presence of an al-kylene oxide optionally substituted with an alkyl group, in particular in a solvent such as dichloromethane, the temperature of reaction being between -80 ° C and the mm boiling temperature of the reaction mixture. 13. The method of claim 11, wherein A and B represent, one, an oxo group, and the other, a dialkoxyphosphinyl group, characterized in that the reaction of the compounds (IV) is carried out and (V) or compounds (VI) and (VII) or compounds (VIII) and (IX), in the presence of a base and, preferably, in the presence of an inert organic solvent, the reaction temperature being included between -80 ° C and the boiling temperature of the reaction mixture. 14. Method according to one of claims 11 to U, characterized in that the compounds obtained by reaction are subjected respectively to compounds of formulas (IV) and (V), compounds of formulas (VI) and ( VII), and compounds of formulas (VIII) and (IX), subsequent functional modifications of the substituent Rg. 15. Medicinal composition, characterized in that it comprises, in a pharmaceutically acceptable carrier, as active substance (s), at least 30 a compound according to one of claims 1 to 10. 16. Composition according to claim 15, characterized in that it is intended for the treatment of dermatological affections linked to a disorder of keratinization and dermatological affections, or others, with an inflammatory and / or immuno-allergic component, in particular at treatment of vulgar, comedonian or polymorphic acnes, senile, solar acne and medicinal or professional acnes, extensive and / or severe forms of psoriasis, and other keratization disorders and, in particular, ichthyoses and ichthyosiform forms, 5 Darier's disease, palmoplantar keratoderma, leukoplakia and leukoplasiform states, lichen planus, all benign or malignant dermatological proliferations, severe or extensive, for the treatment of rheumatoid psoriasis, _______________________________ 10 --- --- to the treatment of cutaneous atopy such as eczema,: and of respiratory atopy, to the treatment of epidermolysis bubble dystrophic uses, molecular pathology of collagen, ultraviolet-induced carcinomas such as solar carcinogenesis, in verruciform epidermodysplasia and related forms, as well as ophthalmological treatments, in particular the treatment of corneopathies. 17. Composition according to one of claims 15 or 16, usable topically, characterized in that the concentration of active substance (s) is between 0.0005% and 2% by weight. 18- Composition according to claim 17, characterized in that the concentration of compost (s) according to one of claims 1 to 10 is between 0.002 and 1% by weight. 19- Composition according to one of claims 17 or 18, characterized in that it is in the form of ointment, gel, cream, ointment, powder, tincture, solution, suspension, d emulsion, 30 lotion, spray, patch and soaked tampon. 20. Composition according to one of claims - 15 to 19, characterized in that it is administered i by ocular route, in particular in the form of eye drops. 21. Composition according to one of claims 35 15 or 16, characterized in that it is administrable 46 enterally, in particular in the form of tablets, capsules, dragees, syrups, suspensions, solutions, powders, granules and emulsions, or parenterally, in particular * in the form of solutions or suspensions for infusions 5 or for injections, at a rate of 2 JAg to 2 mg of compound (s) according to one of claims 1 to 10, per day and per kg body weight. 22. Composition according to one of claims 15 to 21, characterized in that the pharmacologically acceptable carrier of the composition contains at least; a product taken from the group formed by water, gelatin, lactose, starch, talc, petroleum jelly, gum arabic, polyalkylene glycols, magnesium stearate, binders, fillers, diluents, solvents, and thickeners. 23. Cosmetic composition, characterized in that it contains, in a cosmetically acceptable carrier, as active substance (s), at least one compound as defined in one of claims 1 to 10. 20 24 - Composition according to Claim 23, characterized in that it finds an application in body and hair hygiene and, in particular, in the treatment of acne-prone skin, physiologically dry skin, seborrhea, hair loss, for 25 regrows hair, in the treatment and prevention of the harmful effects of the sun and to fight against the greasy appearance of the skin and hair. 25. Composition according to claim 23 or 24, characterized in that the active substance (s) is (or are) present at a concentration between 0.0005 and 2 % by weight and preferably between 0.01 and 1% by weight. 26. Composition according to one of claims 23 to 25, characterized in that it is in the form of a lotion, gel, cream, soap or shampoo. i, 47 *% 27. Composition according to one of claims 15 to 26, characterized in that it contains inert additives or pharmacodynamically or cosmetically active additives taken from the group formed by hydrating agents, anti-aging agents. seborrheic, anti-acne agents, antibiotics, agents promoting hair regrowth, anti-inflammatory agents, carotenoids, anti-psoriatic agents, flavoring agents, preserving agents, stabilizing agents , humidity regulating agents, pH regulating agents, osmotic pressure modifying agents, emulsifying agents, UV-A and UV-B filters and antioxidants. Drawings: ......... ^ ...... boards kS pages of which ....... A ....... cover page .......... .pages of description ...... Aâ ...... pages of claim ........ A ..... short description Luxembourg, Is -6 m 19e6 The representative: Me Alain Rukavina